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Circ Res. 2008 Sep 12;103(6):671-9. doi: 10.1161/CIRCRESAHA.108.182097. Epub 2008 Jul 31.

p21-activated kinase signaling regulates oxidant-dependent NF-kappa B activation by flow.

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  • 1Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.


Disturbed blood flow induces inflammatory gene expression in endothelial cells, which promotes atherosclerosis. Flow stimulates the proinflammatory transcription factor nuclear factor (NF)-kappaB through integrin- and Rac-dependent production of reactive oxygen species (ROS). Previous work demonstrated that NF-kappaB activation by flow is matrix-specific, occurring in cells on fibronectin but not collagen. Activation of p21-activated kinase (PAK) followed the same matrix-dependent pattern. We now show that inhibiting PAK in cells on fibronectin blocked NF-kappaB activation by both laminar and oscillatory flow in vitro and at sites of disturbed flow in vivo. Constitutively active PAK rescued flow-induced NF-kappaB activation in cells on collagen. Surprisingly, PAK was not required for flow-induced ROS production. Instead, PAK modulated the ability of ROS to activate the NF-kappaB pathway. These data demonstrate that PAK controls NF-kappaB activation by modulating the sensitivity of cells to ROS.

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